OCULAR MANIFESTATIONS OF VON HIPPEL–LINDAU DISEASE: CLINICAL AND GENETIC INVESTIGATIONS BY Emily Ying Chew MD ABSTRACT Purpose: To describe the clinical spectrum of lesions involving the visual system in von Hippel–Lindau (VHL) disease, the genetic alterations, and the molecular genetic properties of retinal hemangioblastomas. Methods: In this prospective case-series, 406 patients with VHL disease had systemic and ocular evaluations. Genetic mutations within six pathological specimens were evaluated, using microdissection and polymerase chain reaction amplification. Results: Half of the 406 patients (199 families) with VHL disease had ocular involvement. Visual acuity was 20/20 or better in 170 patients (84.5%) with hemangioblastomas; six (3%) were legally blind. Thirty-three (8.2%) had unilateral enucleations. Genetic mutations were detected in all VHL patients. The patients with complete deletion were less likely to have ocular VHL compared with those patients with partial deletion, missense, and nonsense mutation (9% versus 45%) (P < .0001), suggesting the importance of the gene or areas of genes on chromosome 3 for the development of retinal hemangioblastomas. The molecular genetic assessments of the pathology specimens showed that the foamy “stromal” cells were affected with the genetic mutations. There is an up-regulation of vascular endothelial growth factor, which was expressed in the ocular lesions. Conclusions: In this series, the largest of its kind, patients with ocular lesions of VHL disease are referred mostly from physicians. The systemic genetic mutation evaluations suggest that a certain gene or groups of genes in chromosome 3p are crucial for both the development and maintenance of the retinal tumor. This is the first series to find a difference between the phenotype and genotype. Trans Am Ophthalmol Soc 2005;103:495-511 INTRODUCTION The ocular manifestations of von Hippel–Lindau syndrome (VHL), consisting of retinal capillary hemangioblastomas, have a clinical appearance that is both characteristic and diagnostic of VHL. These ocular lesions have stimulated interest among ophthalmologists throughout the ages, as witnessed by the extensive literature on VHL. The intents of this report are twofold: (1) to describe the clinical manifestations of VHL from one institution in which patients do not present because of ocular symptoms but rather because of known systemic VHL involvement, and (2) to discuss genetic assessments of all patients with VHL and specific vascular lesions in selected cases. These data are integrated in an effort to better understand the development and evolution of the ocular lesions and to propose potential therapies for the potentially blinding ocular disease of VHL. In this thesis, the term “retinal hemangioblastoma” is used to denote the typical lesion seen in these patients. Various investigators have used other terms, including “capillary hemangioma” and “retinal angioma.” Although the term retinal angioma may be better known to both ophthalmologists and medical colleagues, hemangioblastoma may be more accurate, because it corresponds to the pathological aspects of the lesion. HISTORY OF VON HIPPEL-LINDAU DISEASE One hundred years ago, Eugen von Hippel (1867–1938), a German ophthalmologist, published descriptions of retinal hemangioblastomas transmitted through several generations of family members in a small number of kindreds. 1 A number of incomplete descriptions, as well as illustrations, of hemangioblastomas of the eye and vascular lesions in the cerebellum had been reported before 1904. In 1926, the Swedish pathologist Arvid Lindau established the link between retinal and cerebellar hemangioblastomas as well as the findings of cysts in the kidney, pancreas, and epididymis as part of a familial syndrome. 2 The landmark summary in 1964 by Melmon and Rosen established the first clinical diagnostic criteria for VHL. 3 Linkage of the VHL gene to the short arm of chromosome 3 was reported by Seizinger and colleagues in 1988. 4 Finally, in 1993, Latif and colleagues identified the VHL tumor suppressor gene. 5 EXTRAOCULAR CLINICAL FINDINGS OF VON HIPPEL-LINDAU DISEASE VHL is an autosomal dominant neoplastic disorder in which multiple benign or malignant tumors and cysts with specific histopathologic features develop in the tissues of the central nervous system, including brain, spinal cord, inner ear, and retina, and in visceral organs, including kidney, adrenal gland, pancreas, epididymis, and broad ligament. 6-17 The disease results from germline mutation in the VHL gene, which is located on the short arm of chromosome 3, 3p25-26. 5 VHL is a rare disorder (with an approximate incidence of 1 in 36,000 live births) and has a penetrance of over 90% by 65 years of age. 18,19 Prior to the development of routine comprehensive screening surveys, the median survival of patients with VHL was less than 50 years of age and the main causes of death were complications associated with renal cell carcinomas and central nervous system hemangioblastomas. 9,20-22 Improved surveillance, earlier diagnosis of lesions by modern imaging and laboratory studies, From the National Eye Institute, National Institutes of Health, Bethesda, Maryland. Trans Am Ophthalmol Soc / Vol 103/ 2005 495
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